Lecture 11 - Neurotrophic Factors II Flashcards
What are the Statistics for Parkinson’s disease?
- 2nd most common neurodegenerative disorder after Alzheimer’s disease.
- Incurable & progressive disease.
- Afflict 0.3% of the general population worldwide.
- Occurs in all ethnic groups.
- Appears to be somewhat more common in men
- Associated with significant disability & substantial decrease in quality of life.
- Increase with age
What is the Diagnosis for Parkinson’s?
Mostly Idiopathic/sporadic & < 10% familial parkinsons.
Definition
Asymmetry with
- Resting tremor.
- Rigidity.
- Bradykinesis.
- Postural instability (non-specific & usually absent in early state of disease).
- Increasing evidence of non-motor dyfunctions before motor signs of Parkinson’s disease -
Patients also exhibit sleep disturbance, autonomic dysfunction, hyposmia, cognitive decline and depression.
Other characteristics of PD
- Presence of “Lewy bodies” in the neurons of SN — postmortem
- 75% of PD patients have LB — not all.
- What is in these neuron — apoptosomes/ and other proteins
- α-synuclein: Not definitive for PD, Incidental α-synuclein pathology in the normal aging brain, with frequencies of 8%—22.5% in normal aging and 34.8% in centenarians
Appears that “more than one road lead to Rome”.
i.e., PD is a syndrome of multiple causes
AnnRevMed 55:41-60
Other “Parkinsonism” with similar symptoms
What are ther clinical syndromes showing some similarities?
- Subcortical degenerations (e.g., Huntington’s disease, progressive supranuclear
palsy). - Cortical degenerations (e.g., Alzheimer’s disease, CJD, hydrocephalus).
- Encephalitis (e.g., Encephalitis lethargica, viral infections).
- Toxins (e.g., MPTP, CO, pesticides)
- Drugs (e.g., Dopamine receptor blockers).
Proposed model of development of premotor symptoms
u Comparison among persons who will or will not develop PD in lifetime
What does it show?
Significant number of DA neuron would have died at point of diagnosis
What regions are affected in Parkinson’s disease?
Basal ganglia - dopaminergic neurons
Other neurotransmitter pathways
Other areas
What makes substantia Nigra DA neuron vulnerable?
Disproportionately large toxic burden (a-synuclein ) on the machinery for cellular transport and synaptic release.
Each human SNC DA neuron
1-2.5 million synapses in the striatum
Total axonal length in > 4 m
What is a chemotherapeutic for Parkinson’s disease?
L-Dopa (precursor to dopamine)
But 10-14% of patients on dopamine agonists: impulse-control disorders, turning some into gamblers.
What are the traits of L-Dopa Therapy?
- Managing disease
- ‘Honey-Moon’ years
- Efficacy decline with progression of disease
- Dosage titration is difficult in late stages. Side effects
What protects neuron from dying in S. NIGRA?
GENETICS V. ENVIRONMENTS
Protective effects noted for:
- cigarette smoking, a/coho/and caffeine intake.
Unclear how they influence disease risk
Not magic but science
- Caffeine — largely act as brain adenosine A2A receptor (A2AR) antagonist
- Istradefylline (FDA approved 2019) as a ‘levodopa sparing’ strategy
How does MPTP cause signs of Parkinsonism?
Goes inside glial cells, becomes oxidised, goes inside dopaminergic neurons and blocks enzymes in respiratory system
What are other forms of Chemical induced Parkinsonism?
Paraquat - herbicide
Rotenone
- Rotenone — Mitochondrial inhibitor
- 6-OH-DA — inject into striatum & retrogradely destroy SN neuron
- Proteosome inhibitors (inhibit “protein handling”) e.g. Epoxomycin
How do genes influence PD?
Some Genes involved in familial PD
- Majority of PD -idiopathic (90—95%) with no specific known cause
- 5-10% remaining ones are familial forms
What are some Proposed mechanisms/ interactions in the dopaminergic cells of the substantia niqra in PD?
Principle defects
- Misfolding/inclusion body.
- Metabolism
- Protein turn-over
- Impaired intracellular trafficking
International conference on harmonization (ICH) - 1990
US/ EUROPE/ JAPAN
What was it about?
Development of a COMMON TECHNICAL DOCUMENT (CTD) - standardizing global drug application procedures.
Reduce duplication of preclinical/clinical requirements for new drugs/medicine — expedite drug acceptance in different countries.
Safeguards on:
- Quality
- Safety
- Efficacy
- Regulatory obligations to protect pubic health.
What are the different Therapeutic molecules?
“Conventional drugs” (Pharmaceuticals)
Synthetic
o Known structures
o Small organic molecules
Biologics (Biopharmaceuticals)
Derived from living sources
o Bacterial/ viral vaccines
o human blood/plasma derivatives.
o Tissues.
o Biotechnology derived products — monoclonal antibodies, cytokines, growth factors, gene therapy
Why is discovering drugs a long & expensive process?
Most drugs that go through die along the way, but the earlier the better because it gets more and more costly
What are the results of the Bristol study using GDNF for PD?
RESULTS: Phase I — “open label trial”
- Safe
- UPDRS/PDQ-39 assessment — significant improvements.
- Promising approach — 5 patients.
Why might there be contradictory results using GDNF for PD?
Each trial is different in GDNF infusion techniques, GDNF dosing regimens,and clinical study designs.
ISSUE I: Bioavailability of convection-enhanced delivery of GDNF
Pharmacokinetics - how drug get there
How is a constant therapeutic level obtained when drug is continuously eliminted?
Multiple dosage
Bioavailability
What is it evaluated based on?
What are the factors involved?
Evaluated based on two measures
- Rate of absorption
- Extent of absorption
Factors involved:
- Absorption
- Distribution
- Elimination
What are some method of drug delivery?
Previous methods: ‘bolus’, Intracerebral ventricular delivery
- Continuous delivery-require: a reliable prediction method coupled to a fluid delivery device and a sufficiently large drug reservoir.
- Convection-enhanced delivery (CED): drug-delivery technique using positive hydrostatic pressure to deliver a fluid containing drug by bulk flow directly into localized region.
- Circumvents the blood-brain-barrier and provides a wider, more homogenous distribution than bolus deposition (focal injection) or other diffusion-based delivery approaches.
What are some other issues regarding the use of GDNF for PD?
ISSUE Il: Placebo effect (may not be true as increase in DA innervation in SN)
ISSUE Ill: +ve 18F-dopa uptake does not necessary mean dopaminergic neurons are functional (other biomarkers?). To be truly beneficial for PD, other neurotransmitter/neurowiring systems (glutamate, GABA, adenosine) should also be addressed.
ISSUE IV: autoantibodies (reduce bioavailability).
ISSUE V: Safety issues —cerebrellar pathologies in animal models
Bioavailability is a limitation in delivering GDNF.
Gene therapy
How did CERE-120 — AAV2 mediated delivery of NTN show promise.
38 treated patients & 20 control patients (sham surgery) — no difference in
primary endpoint—the motor subscore of the UPDRS at 12 months.
19 of treatment but no control patients showed significant positive changes
after 18 months!!
What limited the therapy (NTN) and why some trials did not work before?
Post mortem of 2 patients from trial.
Look for expression of NTN in CERE-120 in putamen: high
Look for NTN in substantial nigra: low
Parkinson’s Disease Brains do not transport neurturin well — problem with axonal transport.
Speculation: a-synuclein aggregation/deposition observed in the transplanted dopaminergic neurons was triggered by misfolded a-synuclein in the host, transmitted into grafted cells.
How can this happen?
- Accumulating evidence from cell-culture: a Synuclein (PARK1/PARK4) aggregates can be endocytosed into cells and accumulate.
Study showed:
- in vivo transfer of a-synuclein to dopaminergic neurons grafted to the striatum of transgenic mice overexpressing human a-synuclein, i.e., a paradigm like that of the PD cases exhibiting Lewy Body pathology in grafted cells.
- Result: intercellularly transferred a-synuclein may display a prion-like behaviour? - playing a central role in the progression of Parkinson’s disease.
But not all graft showed a-synuclein
Stem cell/derivatives as PD treatment?
Directed differentiation of the human iPSC using trophic factors & cells secrete neurotrophic factors & anti-inflammatory effects
o Promising results: non-human primate implanted iPSC derived DA neuron
o 2020. 5 yr follow-up, 1st in Man (hNPC), safe.
o 2021. hES derived DA producing neuron
o STEM-PD (ES derived DA progenitor. Oct 2022. Phase 1/11)
